SPARC-Independent Delivery of Nab-Paclitaxel without Depleting Tumor Stroma in Patient-Derived Pancreatic Cancer Xenografts

Abstract

The study goal was to examine the relationship between nab-paclitaxel delivery and SPARC (secreted protein acidic and rich in cysteine) expression in pancreatic tumor xenografts and to determine the anti-stromal effect of nab-paclitaxel, which may affect tumor vascular perfusion. SPARC positive and negative mice bearing Panc02 tumor xenografts (n=5–6/group) were injected with IRDye 800CW (IR800)-labeled nab-paclitaxel. After 24 hours, tumors were collected and stained with DL650-labeled anti-SPARC antibody, and the correlation between nab-paclitaxel and SPARC distributions was examined. Eight groups of mice bearing either Panc039 or Panc198 patient-derived xenografts (PDXs) (4 groups/model, 5 animals/group) were untreated (served as control) or treated with gemcitabine (100 mg/kg BW, i.p., twice per week), nab-paclitaxel (30 mg/kg BW, i.v., for 5 consecutive days), and these agents in combination, respectively, for 3 weeks, and tumor volume and perfusion changes were assessed using T2-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced (DCE) MRI, respectively. All tumors were collected and stained with Masson’s Trichrome Stain, followed by a blinded comparative analysis of tumor stroma density. IR800-nab-paclitaxel was mainly distributed in tumor stromal tissue, but nab-paclitaxel and SPARC distributions were minimally correlated in either SPARC positive or negative animals. Nab-paclitaxel treatment did not decrease tumor stroma nor increase tumor vascular perfusion in either PDX model when compared to control groups. These data suggest that the specific tumor delivery of nab-paclitaxel is not directly related to SPARC expression, and nab-paclitaxel does not deplete tumor stroma in general.

Roles of Albumin‐Binding Proteins in Cancer Progression and Biomimetic Targeted Drug Delivery

“…However, there are contradictory reports that raise the question of whether SPARC is associated with the therapeutic effect of Abraxane. For example, a study showed that Abraxane was preferentially delivered to tumor stromal tissue, but there was a minimal correlation between Abraxane and SPARC distribution in either SPARC‐positive or ‐negative animals, which suggested that the specific tumor delivery of Abraxane was not directly related to SPARC expression …”

“…For example, as tudy showedt hat Abraxane was preferentially delivered to tumor stromal tissue, butt here was am inimal correlation between Abraxane and SPARC distribution in either SPARC-positive or -negative animals, which suggested that the specific tumor delivery of Abraxane was not directly relatedt oSPARC expression. [75] Figure 6. A) BBB-penetrating l-BSA NPs delivered into gliomathrough mechanisms targeting the ABP;the efficiency is furthere nhanced by cell-penetrating peptide( CPP)-assisted penetration.…”

Animal models of pancreatic cancer and their application in clinical research

“…47 Further to this, Roy Chaudhuri et al investigated the effect of smoothened inhibitors of hedgehog signaling (sHHI) to overcome the stromal barrier and promote neovascularization and enhance tumor permeability to low-molecular weight compounds in a PDX model of pancreatic cancer. The authors demonstrated that sHHI can enhance tumor deposition and efficacy of drug-containing nanoparticles consisting sterically stabilized liposomes containing doxorubicin.…”

Nab‐paclitaxel interrupts cancer‐stromal interaction through C‐X‐C motif chemokine 10‐mediated interleukin‐6 downregulation in vitro

“…Nab‐PTX, approved by the Food and Drug Administration (FDA) in 2012 as the first line in neoadjuvant therapy for pancreatic cancer, is widely used in clinical work and significantly improves outcome . Taking advantage of albumin‐binding, nab‐PTX efficiently accumulates in peri‐ and intratumoral areas dependent or independent of secreted protein acidic and rich in cysteine (SPARC) mediating . Many clinical and animal studies showed that nab‐PTX treatment could disrupt tumor stroma, decrease PSC activity, and inflammatory cytokines .…”

“…8 Taking advantage of albumin-binding, nab-PTX efficiently accumulates in peri-and intratumoral areas dependent or independent of secreted protein acidic and rich in cysteine (SPARC) mediating. 9,10 Many clinical and animal studies showed that nab-PTX treatment could disrupt tumor stroma, decrease PSC activity, and inflammatory cytokines. 11 However, the role of nab-PTX in tumor cells and CAF communication is unclear.…”